The present invention relates to a pharmaceutical oral composition for the controlled release of the active ingredient comprising a multiplicity of microgranules or small pellets, each consisting of a core of active ingredient and binder and of a membrane applied on said core of active ingredient, able to release said drug at successive times at a substantially regular rate. More particularly, the present invention relates to microgranules comprising a core containing bile acid and binder and thereon a membrane able to release the active ingredient at successive times at a substantially regular rate within the 12th hour starting from the time of administration, as well as a process for preparing the same.
As alkaline metal salts, the bile acids are compounds with a common steroid structure representing about 1% of mammals bile.
The bile acids are characterized by a) the presence of a side chain with 5 carbon atoms at C-17, the last of which bears an acid group, b) the presence of an hydroxylic group in C-3. The in nature occurring bile acids appear as derivatives conjugated with lysine or taurine and, in relation to the environment pH, as alkaline salts. Accordingly, they are also named sodium glycolates or taurocholates. In the human beings the bile acids are cholic, deoxycholic, chenodeoxycholic and respectively lithocholic acid. In bears' bile ursodeoxycholic acid was then found, that is the chenodeoxycholic acid epimer, whereas the 7-alpha-ketolithocholic acid was synthetically obtained. They arise chemically from cholanic acid, not occurring in nature but that can be obtained from cholesterol.
The bile acids are elaborated at liver level, starting from cholesterol, and are secreted by bile in the gut. They are partially destroyed by the enzimes of bacteric origin and mostly brought again to the liver by the vena cava (cycloenteroepatic). They are water soluble at the conjugated state. In phosphoric or sulfuric environment they are displaced from cholalic acid and impart a blue fluorescence to the medium, and with several aldehydes they yield colourings utilizable in quantitative analysis: the Pettenkofer's reaction with hydroxymethylfurfural produced by saccharose and the Charronat' reaction, in which vanilline is involved.
Moreover, the bile acids exhibit a softening activity, lower the surface tension in aqueous solvents, said phenomenon explaining the bile emulsive power and it s participation at the start of fats digestion, their attack being thus facilitated by means of the pancreatic secretion. This surface-active activity is inhibited by proteins.
Usually, the bile acids are not present in urine, except for the case of icterus, in which first biliary pigments can appear; they can be ascertained owing to their surface-active properties (the "sulphur flower" floats on a bile acids-containing liquid). In the blood, the bile acids rate (cholalemia) is very low, but in case of icterus it increases considerably. Cholalemia may be estimated by means of colorimetry or spectrometry of the above described reactions or by fluorometry. In therapy, biliary salts are employed (cholic and deoxycholic acid) in which bile is "depigmented": per oral route they act as cholagogues or as adjuvants in lipids digestion (chenodeoxycholic acid is a solvent for gall stones), whereas for rectal route they are administered as suppositories and in washings as mechanical laxatives owing to their ability to cause intestinal contractions. In the pharmaceutical industry they and bile play an important role in the manufacturing of steroidal hormones.
Since about twenty years, it is common practice to administer bile acids for denaturating lithogenous bile supersaturated with cholesterol and consequently for obtaining also the lysis of already formed cholesterol calculi. Said therapy should be continued for long periods of time, generally ranging from six months and two years.
Logically, this prolonged therapy is enormously facilitated by controlled release compositions permitting to administer daily to a patient only a unit dose form or two in particular cases.
Thus in IT-A-1.101.649 a pharmaceutical composition for oral use in the form of tablets is described, containing a bile acid as active principles in an amount of maximal 600-750 mg and adapted to lyse calculi of cholesterol origin. From these compositions the active principle can be released over a protracted time period. As bile acids, ursodeoxycholic chenodeoxycholic and 7-alpha-ketolithocholic acid are mentioned.
Now it is known that in comparison with tablets, compositions in the form of microgranules or pellets exhibit several advantages. In particular, hard gelatine capsules are filled with microgranules of active ingredient, and a few minutes after ingestion said capsule dissolves, thus permitting a complete releasing of the microgranules in the stomach and afterwards through the gastrointestinal tract and so removing the side effects and making easier the absorption in comparison with controlled release tablets (see for example Bechgaard H., Critical factors influencing gastrointestinal absorption--What is the role of pellets!, Acta Pharmaceutica Technologics, 28 (2) 1982, 149-156; Bechett A. H., Important formulation factors influencing drug absorption, Department of Pharmacy, Chelsea College, University of London; Wilson C. G. and Washington N., Assesment of disintegration and dissolution of dosage forms in vivo using gamma scintigraphy, Drug Development and Industrial Pharmacy, 14 (2 & 3), 211-281, 1988. Thus in US-A-2.918.411 a pharmaceutical composition for oral administration is described, comprising essentially a multiplicity of small pellets consisting of (a) polyvinylpyrrolidone, (b) a water soluble agent melting above 45.degree. C. and selected from the group consisting of saturated fatty acids, saturated fatty acids esters of mono, di and tri-hydroxylated alcohols, mono and polyesters of saturated fatty acids, saturated aliphatic ketons and pharmaceutically acceptable sterols, and (c) a drug.
From BE-A-838.505 microcapsules able to release nitrogen to ruminants are known, wherein the active ingredient is coated with a paraffin and polyethylene film able to release the active ingredient within a predetermined period of time.
In US-A-4.572.833 a pharmaceutical oral controlled release composition is described, in which potassium chloride microgranules are coated with a membrane comprising a solvent, film-forming substance dissolved in the solvent and a hydrophobic substance microdispersed in film-forming mixture.
In FR-A-2.237.620 a depot galenic form for the oral administration of drugs is described, comprising spherical drug particles coated with a membrane consisting of (a) methylcellulose, ethylcellulose or propylcellulose, (b) a polymer of methacrylic acid and methacrylic acid esters (Eudragit L), cellulose phthalate, hydroxypropyl methylcellulose phthalate, lac, gum arabic, rosin, palmitic acid, myristic or stearic acid. Further patents describing pharmaceutical oral compositions comprising microgranules of active ingredient coated with a membrane able to release with the time said active ingredient are GB-A-1.413.186, GB-A-595.444 and FR-A-1.329.120.
In no one of the mentioned patents or in the above cited literature pharmaceutical oral compositions in the form of coated microgranules or pellets are described, containing bile acids as active ingredient.
Therefore, it was object of the present invention to provide pharmaceutical oral controlled release compositions comprising a multiplicity of microgranules or pellets each consisting of a core of active ingredient and binder and of a membrane able to release the drug at successive times at substantially regular rates. It was in particular object of the invention to provide a composition comprising microgranules coated with a particular membrane above to uniformly and uninterruptly release more than 500 microgranules per capsule in the gastrointestinal tract, thus enhancing absorption and in this way the pharmacological effect in comparison with the known tablets.